LETTERS

sistent in one patient for 12 months after withdrawal of procainamide; a spontaneous remission now lasting 1 year then ensued. In the other patients, hypocomplementemia and arthritis did not last longer than 6 months after withdrawal of procainamide, and there has been no recurrence of any signs or symptoms of systemic lupus erythematosus during 2 years of follow-up. Synovial fluid analysis, previously undescribed in procainamide-associated systemic lupus erythematosus was done in four of five patients. In all patients, there was a straw-colored exudate, and a leukocyte count was less than 2000/mm 3 with greater than 50% mononuclear cells. The synovial fluid C3 was less than 30 mg/dl in all four patients, with a mean of 22 mg/dl; the simultaneous serum Hypocomplementemia in Procainamide-Associated C3 was greater than 70 mg/dl. These findings are similar to Systemic Lupus Erythematosus those in idiopathic systemic lupus erythematosus ( 4 ) . Procainamide-associated systemic lupus erythematosus PROCAINAMIDE is the most potent drug capable of inducing a systemic lupus erythematosus-like syndrome ( 1 ) . The resembles idiopathic systemic lupus erythematosus in many respects. In the individual patient, it is impossible to disdistinction of this syndrome from idiopathic systemic lupus tinguish procainamide-associated systemic lupus erythemaerythematosus is based on [a] a different incidence of clintosus from idiopathic systemic lupus erythematosus coinical manifestations (procainamide-associated lupus erythecidently occurring in a patient receiving procainamide. The matosus is rare in blacks, affects an older population, and occurrence in one patient of dermal-epidermal immunorarely results in renal disease); [b] the absence of antifluorescent staining for immunoglobulins and complement bodies to native D N A and normal serum complement stresses again that this pathologic feature cannot differentilevels; and [c] clinical improvement after withdrawal of the ate idiopathic lupus erythematosus from procainamide-asdrug (2, 3 ) . In the individual patient, however, the clinical sociated lupus erythematosus ( 5 ) . Our findings emphasize manifestations may be identical to those in idiopathic lupus that hypocomplementemia cannot be used to distinguish erythematosus, and symptoms may last for years. Thus, procainamide-associated lupus erythematosus from idiothe diagnosis and subsequent prognosis is based, to a large pathic lupus erythematosus. Thus, it appears that absence extent, on the absence of D N A antibodies and the absence of antibodies to native D N A remains the most reliable of serum hypocomplementemia. diagnostic feature of procainamide-associated lupus eryWe have had the opportunity to study five patients with thematosus. procainamide-associated systemic lupus erythematosus with PETER D. UTSINGER, M.D. the rare finding of hypocomplementemia. All were white NATHAN J. ZVAIFLER, M.D. men, and their average age was 62 years. The average HARRY G. BLUESTEIN, M.D. duration of therapy before symtoms began was 10 months, with a range of 2 months to 3 years. The mean daily dose Division of Rheumatology and Clinical Immunology Department of Medicine of procainamide at the time symptoms developed was 2 University of North Carolina grams. At initial presentation, all of the patients had Chapel Hill, North Carolina 27514 arthralgias or arthritis. Three were febrile, two had a pleural effusion, and another had a pericardial effusion. University Hospital No patient had renal disease or abnormalities on urinalysis. University of California, San Diego Hemagglutinating antibodies to native D N A were not deSan Diego, California 92103 tected by incubating the test serums with human 0 + cells Received 3 November 1975. coated with native DNA. In one patient, deposition of IgG, IgM, and complement at the dermal-epidermal juncREFERENCES tion of normal-appearing skin was documented by direct 1. ALARCO'N-SEGOVIA D: Drug-induced lupus syndromes. Mayo Clin immunofluorescent staining. Two patients had a positive Proc 44:664-681, 1969 direct Coombs' test. 2. DUBOIS EL: Procainamide induction of a systemic lupus erythematosus-like syndrome. Medicine (Baltimore) 48:217-228, 1969 Serum complement was studied in these five patients. All 3. BLOMGREN SE, CONDEMI J J, VAUGHAN JH: Procainamide-induced had hypocomplementemia as determined both by a hemolupus erythematosus. Clinical and laboratory observations. Am lytic complement assay and by mild reduction of C3 or C4. J Med 52:338-348, 1972 4. PEKIN TJ, ZVAIFLER NJ: Synovialfluidfindingsin systemic lupus The CH50 ranged from 68 to 88 U/ml (normal, > 120 U / erythematosus (SLE). Arthritis Rheum 13:777-785, 1970 ml), C3 ranged from 70 to 110 mg/dl (normal, > 90 5. GROSSMAN J, CALLERAME ML, CONDEMI JJ: Skin immunofluoresmg/dl), and C4 ranged from 6 to 15 mg/dl (normal, > 10 cence studies on lupus erythematosus and other antinuclear-antimg/dl). Hypocomplementemia and arthritis were perbody-positive diseases. Ann Intern Med 80:496-500, 1974

Letters that report new clinical or laboratory observations, cases of unusual importance, and new developments in medical care will be considered for publication in this section. Manuscripts must be typed double-spaced. Text length must not exceed 750 words; no more than five references and one figure or table can be used. See "Information for Authors" on page 1-6 for form of references. Manuscripts should include an abstract of length not exceeding 100 words. Letters will be reviewed by consultants when, in the opinion of the editors, such review is needed. The Editor reserves the right to shorten letters and to make changes that accord with our style.

Annals of Internal Medicine 84:293-296, 1976

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Spontaneous Acute Leukemia in Polycythemia Vera ACUTE LEUKEMIA has frequently developed in patients with polycythemia vera. However, its occurrence varies considerably depending on treatment. The occurrence in patients treated with ionizing radiation is higher than that in patients treated with chemotherapy (1) and the "spontaneous" (no leukemogenic exposure) development has been reported only rarely. Because of this discrepancy in the frequency of occurrence, it remains unclear whether acute leukemia is part of the natural history of polycythemia vera, is the consequence of therapy alone, or results from an interaction between these two factors. We treated a man in whom acute leukemia developed after only 4 years of erythrocytosis and in whom treatment for the polycythemia vera consisted of phlebotomy alone. The patient, a 64-year-old machinist, developed erythrocytosis between 1970 and 1971 (Figure 1). In November 1973 he complained of sweats, pruritus, and flushing and was found to have plethora, hypertension, and 3-cm splenomegaly. The hemoglobin was 22 g/dl; hematocrit, 64%; leukocyte count, 8400/mm'; and platelet count, 520 000/mms. The erythrocyte mass was 53 ml/kg; leukocyte alkaline phosphatase score, 183 (normal, 13 to 130); uric acid, 10.6 mg/dl; Bw, 690 pg/ml; bone marrow, hypercellular with increased erythroid elements and megakaryocytes and decreased iron; and the arterial oxygen saturation was 94%. He was treated with phlebotomy but never radiation, ,2 P, or chemotherapy. In October 1974 myeloblasts were seen on the blood smear. During the next 4 months, the leukocyte and blast count continuously rose while the patient became progressively more polycythemic (hemoglobin, 19.8 g/dl). In February 1975 the leukocyte count had reached 98 000/mm* (11% segmented neutrophils, 8% bands, 7% metamyelocytes, 2% myelocytes, 4% promyelocytes, and 58% blasts) and the platelet and erythrocyte count fell. The bone marrow then

was 80% replaced by myeloblasts and cytogenetics showed an abnormal karyotype, 45 X (deleted Y). The acute leukemia was treated with drug-combination therapy (methotrexate, 120 mg/m2 body surface area on Day 1, followed by leucovorin in 36 h; cyclophosphamide, 1 g/m2, and adriamycin, 40 mg/m2 on Day 4; vincristine, 2.0 mg on Day 5; methotrexate, 80 mg/m1 on Day 11; and cytocine arabinoside, 100 mg every 8 h on Days 11 to 14). At the completion of the first cycle, the platelet count rose to 1200 000/mm3 and partial remission was achieved. Repeating the cycle without the initial dose of methotrexate resulted in complete marrow remission that lasted, with monthly maintenance therapy, 5 months. Mild splenomegaly persisted. Despite the maintenance therapy, which included BCG, the acute leukemia relapsed. A partial remission was again achieved with the same regimen, but the patient has since been severely debilitated. This patient had well-documented polycythemia vera and developed acute leukemia after a short course of the polycythemia. There was no history of leukemogenic exposure. During the first 4 months that the leukemic blast count rose, abnormal erythrocyte production continued. Subsequent to successful remission induction, thrombocytosis recurred but the erythrocytosis did not. The 16% occurrence of acute leukemia in patients with polycythemia vera treated with 32P is 20-to-40 times higher than that estimated for a comparable group of healthy people with exposure to similar doses of leukemogenic ionizing radiation ( 1 ) . The true occurrence in the patients treated with alkalating agents, also known to be leukemogenic, is not known but apparently is lower than in the irradiated patients. "Spontaneous" acute leukemia in patients treated only with phlebotomy is rare but has been reported (2-6). Two of these cases ( 3 , 4 ) , like our own, had short intervals between the diagnosis of polycythemia vera and the development of acute leukemia. In only two of the reports (4, 6) was chemotherapy specifically excluded (the emphasis was the exclusion of radiation exposure). This treatment-related difference in the occurrence of acute leukemia in patients with polycythemia vera, not explained by longer survival ( 1 ) , suggests that the causation of the acute leukemia is related to an interaction of factors, one of which is therapy. In our patient, the acute leukemia developed simultaneously with the progression of the erythrocytosis and the thrombocytosis recurred after remission of the acute leukemia, both of which suggested two simultaneous disease processes in different cell lines. The recurrence of polycythemia vera after successful remission induction of acute leukemia in another patient (7) is in keeping with our observation and conclusion in this case. Unfortunately, the chromosomal abnormality found in our patient, which could have been a marker for different cell lines, could not be identified separately in the myeloblast and erythroblast cells. This patient provides another example of acute leukemia's developing "spontaneously" in polycythemia vera and of successful remission induction of the acute leukemia using combination chemotherapy ( 7 ) . The clinical course suggested that in this patient the polycythemia vera predisposed to the development of myeloid leukemia but did not directly transform itself into acute leukemia. W. B. LUNDBERG, M.D.

Figure 1 . Hematological course of patient. Note simultaneous progression of erythrocytosis and leukocytosis ( f t 5 0 % blasts) between October 1974 and January 1975, and marked thrombocytosis after first cycle of chemotherapy; f = platelet transfusion; 4 = erythrocyte transfusion; f = hemorrhage; ^ = phlebotomy; WBC = leukocytes; HCT = hematocrit. 294

March 1976 • Annals of Internal Medicine • Volume 84 • Number 3

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L. R. FARBER, M.D. E. C. CADMAN, M.D. R. T. SKEEL, M.D.

Department of Medical Oncology Yale University School of Medicine New Haven, Connecticut 06510

Table 1. Clinical Data

Received 1 December 1975.

Control

REFERENCES

Pacing

Left Lateral Decubitus

101 85 219 200 ...

66 85 61 70 4.3 5.27 1260

1. GLASS JL, WASSERMAN LR: Primary polycythemia, in Hematology, edited by WILLIAMS WJ,

2. 3. 4. 5. 6. 7.

BEUTLER E, ERSLEW AJ, et al.

New

York, McGraw-Hill Book Co., 1972, p. 538 DAMESHEK W: Physiopathology and course of polycythemia vera as related to therapy. JAMA 142:790-797, 1950 WILLIAMS MT, MENDLE JL: Polycythemia vera terminating with myeloblastic leukemia; correlation of morphologic findings with leucocytic phosphatase studies. Blood 9:189-195, 1954 Clinicopathologic conference. Polycythemia vera complicated by acute leukemia and a rapidly enlarging mass in the left upper abdominal quadrant. Am J Med 42:949-957, 1967 Case Records of the Massachusetts General Hospital. Case 251973. N Engl J Med 288:1343-1350, 1973 ROSENTHAL DS, MALONEY WC: Myeloproliferative disorders with documented leukemia transformation. XV Cong lnt Soc Hematol, 1974, p. 183 NEW LT, SHUMAN MA, BROWN EB: Polycythemia vera and acute leukemia. Ann Intern Med 83:672-673, 1975

Coronary Sinus Blood Flow in Trepopneic Angina: Case Report TREPOPNEA refers to the preference for a particular recumbent position and a dislike of others. In 1937, Wood and Wolferth (1) introduced the term and reported their extensive observations of trepopnea in 52 patients with heart disease, including 3 with positional angina pectoris. We have studied a patient with coronary artery disease in whom the left lateral decubitus position induced angina. Cardiac catheterization was done using a thermodilution coronary sinus blood flow catheter, thus obtaining measurements of coronary blood flow in various body positions. A 41-year-old married practical nurse, gravida 6, para 4, was referred for cardiac catheterization and coronary angiography 6 weeks after sustaining a well-documented, uncomplicated, nontransmural myocardial infarction. She had complained of exertional chest discomfort, relieved by rest, for 2 years before admission. Her symptoms had increased after the myocardial infarction and continued despite the use of nitroglycerin and propranolol. The patient had had hypertension for 2 years and smoked a half pack of cigarettes daily for 23 years. The resting electrocardiogram and vectorcardiogram snowed changes of an inferior myocardial infarction. A treadmill exercise test induced angina and 2 mm of horizontal ST segment depression in lead V4 after 4.4 minutes of exercise that led to a heart rate of 103 beats/min. The patient stated unequivocally that the left lateral decubitus position provoked chest discomfort associated with palpitation, typical of her angina. Her blood pressure was 125/90 mm Hg and pulse, 70 beats/min. She had no skin or tendon xanthomata. Carotid and jugular venous pulses were normal. The left ventricular apical impulse was physiologic. There were no abnormal heart sounds or murmurs. In the left lateral decubitus position, frequent extrasystoles were noted. Serum cholesterol level was 204 mg/dl. Fully informed consent was obtained before catheterization. Cardiac catheterization and coronary angiography (Judkin's technique) were done. A specially designed thermodilution catheter was used to measure coronary sinus blood flow as described by Ganz and associates (2). Each blood flow determination was repeated in duplicate and was reported as the mean. At catheterization, all right and left sided pressures and flows were within normal limits. Selective coronary angiography showed two major obstructions in the left circumflex system. Coronary sinus blood flow was low normal at rest (Table 1)

Heart rate, beats/min 70 Mean arterial pressure, mm/Hg 75 Coronary sinus blood flow, ml/min 89 MV02*, ml On/min 101 3.9 AVCM, vo/% Cardiac output, 1/min 4.84 Systemic resistance, dyn • sec • cm~* 1260 Pulmonary resistance, dyn • sec • cm~b 199

...

but increased markedly with pacing to a heart rate of 100 beats/min. A baseline Fick cardiac output (3 minutes of expired air collection) and hemodynamics were recorded at rest supine. No extrasystoles were found on a continuous electrocardiogram (ECG) recording during the supine Fick collection. The patient was then turned to the 60 ° left lateral decubitus position. After a latent period of approximately 45 seconds, unifocal premature ventricular contractions, with a coupling interval of 430 msec, appeared (R-R interval in sinus rhythm = 990 msec). She then noted mild precordial distress. A second 3-minute expired air collection, coronary sinus blood flow, and hemodynamics were then obtained (Table 1). As shown in Table 1, all hemodynamic determinants were unchanged in the left lateral decubitus position; however, there was a 30% decrease in coronary sinus blood flow. In a previous study in our laboratory (3), in which coronary sinus blood flow measured by thermodilution was compared to coronary sinus blood flow as measured by electromagnetic flow meter in open-chest dogs on cardiopulmonary bypass, a correlation factor of 0.901 was found. Moreover, when coronary sinus blood flow by thermodilution was done multiple times in a given state, duplicate measurements varied by less than 5%, and changes in flow of 20% were statistically significant. By virtue of these data, the 30% decrease in coronary sinus blood flow as measured in the patient is significant. Our data show a marked reduction in coronary sinus blood flow, presumably reflecting a reduction in coronary arterial flow, on assumption of the left lateral decubitus position in a patient with coronary artery disease and trepopnea. The mechanism of this reduction is not immediately evident. There is no positional change in systemic or pulmonary hemodynamics; coronary angiography in both right and left anterior oblique projections showed coronary atherosclerosis but no positional kinking or obstruction. It is conceivable that the coronary sinus catheter is thrust further into the coronary sinus while the patient is in the left lateral position, thus measuring a lower (more proximal) flow; however, every precaution was taken to prevent this artifact. Satisfactory catheter position was confirmed radiologically while the patient was in the left lateral position. Our data thus suggest the presence of heretofore unidentified mechanisms that affect coronary vascular resistance and are activated by body position. Supported in part by U.S. Public Health Service Grant #HL-11306. R. M. MILLS, M.D. G. H. MUDGE, JR., M.D. MICHAEL LESCH, M.D., F.A.C.P.

University of Massachusetts Medical School Worcester, Massachusetts 01605 Letters

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* M V O J = myocardial oxygen consumption. t AVOa = myocardial arteriovenous oxygen difference.

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Cardiovascular Division Peter Bent Brigham Hospital Harvard Medical School Boston, Massachusetts 02115 Received 4 December 1975, REFERENCES 1. WOOD FC, WOLFERTH CC: The tolerance of certain cardiac pa-

tients for various recumbent positions (trepopnea). Am J Med Sci 193:354-378, 1937 2. GANZ W, TAMURA K, MARCUS H, et al: Measurement of coronary

sinus blood flow by continuous tbermodilution in man. Circulation 64:181-195, 1971 3. VAN DEVANTER S, MILLS R, LESCH M, et al: Thermodilution

measurement of coronary sinus blood flow during cardiopulmonary bypass. Surg Forum 26:225-227, 1975

Carbamazepine in Uremic Neuropathy CARBAMAZEPINE (Tegretol®)* has been used by us in five patients with severe uremic neuropathy where pain was the dominating symptom. All patients were on chronic hemodialysis. They had been taking a number of oral analgesics previously (acetominophene, propoxyphene), with or without codeine, without significant relief. Carbamazepine was started with a dose of 100 mg twice daily and increased to 200-to-300 mg twice daily if necessary. All five patients reported relief of pain after 1 or 2 weeks of treatment. In no case did we have to give more than 600 mg (three tablets) a day. Other symptoms of uremic neuropathy, i.e., * Geigy Pharmaceuticals, Ardsley, New York.

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motor weakness and paresthesias, have not changed appreciably during the period of observation. Two patients complained of drowsiness or sleepiness, but treatment was continued. Weekly determinations of complete blood counts with differentials were done. The drug was discontinued in one patient when the white blood count fell below 4000 mm 3 . Treatment was re-instated at a lower dosage level. Other side effects were not observed. After the first two weeks, there was no further increase in dose requirements and there were no secondary failures. This trial obviously was not controlled. We are aware of the difficulties of assessing drug action where pain is the symptom. We also know that carbamazepine has an antidepressant effect which may contribute to the present action. However, we believe that our experience should be reported to the profession since uremic neuropathy is a chronic, progressive, debilitating condition and very often a cause of severe despair. In this situation any source of hope is welcome. ZOLTAN ZARDAY, M.D. ROBERT J. SOBERMAN, M.D.

Bronx Dialysis Center Bronx, New York 10467 Received 8 December 1975. Pain of uremic neuropathy is not among the indications for carbamazepine given on its current FDA-approved package insert; physicians contemplating its use for this type of pain should be aware that such trials must be regarded as experimental.—The Editor

March 2976 • Annals of Internal Medicine • Volume 84 • Number 3

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Spontaneous acute leukemia in polycythemia vera.

LETTERS sistent in one patient for 12 months after withdrawal of procainamide; a spontaneous remission now lasting 1 year then ensued. In the other p...
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